Atopic eczema/dermatitis syndrome – a genetically complex disease. New advances in discovering the genetic contribution

Due to recent developments in molecular genetics great progress has been achieved in understanding the etiology of human genetic diseases. Presumably, most causative genes for monogenic diseases will be known within the next few years. However, this progress is mainly limited to the rare monogenic diseases. Since Cloninger (1) – searching for genes predisposing to schizophrenia – stated a complex hypotheses about the inheritance of schizophrenia, a shift within medical genetics started, from the focus on monogenic diseases to genetically complex diseases. Still, in most contexts, talk about being postgenomic seems a little premature. Post-Mendelian seems more accurate as we move from an era in which genetics has been rooted in monogenic diseases with high penetrance to a greater awareness (but limited understanding) of polygenic diseases and traits often with relatively low penetrance. The etiology of complex diseases is multifactorial and based on several interacting genetic mechanisms and additional environmental factors. Today, many diseases like arterial hypertension, diabetes mellitus, inflammatory bowel disease, epilepsy, schizophrenia, migraine, psoriasis, asthma and atopic eczema/dermatitis syndrome (AEDS) are seen as genetically complex. Generally, they have a much higher population prevalence than the rare monogenic diseases, hence an improved understanding of the pathology of complex diseases is highly relevant in socioeconomic terms. The present review is aimed to focus on research results on AEDS as a complex disease with a multifactorial pathophysiologic background. The nomenclature of allergic diseases is used according to the EAACI Nomenclature Position Paper (2). Atopic eczema/dermatitis syndrome (AEDS) is a common chronic inflammatory skin disorder that is regarded as a typical multifactorial disease. The etiology is complex and the disease is caused by concerted actions of environmental and genetic factors. A unifying causal and formal pathogenetic concept of AEDS has still not been established (3). The interactions between genetic and environmental mechanisms are largely unknown (4). Linkage of AEDS, allergic asthma, allergic rhinitis, and total serum IgE levels to several different chromosomal regions have been described extensively, but little is known about the contributing gene loci and their variants. Like allergic asthma and allergic rhinitis AEDS became one of the most frequent diseases in populations of civilized countries (5, 6). In the past three decades an increasing prevalence was observed especially in industrialized populations (7, 8). This cannot be explained on the basis of genes alone (9), but reveals a multifactorial pathogenetic concept characteristic for complex diseases, depending on both environmental and genetic factors (10). Environmental allergen levels are probably the major determinant of whether sensitization of genetically predisposed individuals occurs. Increased exposure to sensitizing allergens and reduced stimulation of the immune system during critical periods of development (11) are seen as the main factors driving the rising prevalence of allergic diseases. The IgE-mediated antigen presentation of (aero-) allergens has been recognized as a key event in the pathogenesis of AEDS (12). There may be several genetic factors varying in different populations because there is not one single gene responsible for the disease like in monogenetic illnesses. In addition, imprinting, e.g., parent of origin effects may play a role in etiology, and have been observed in a number of population studies (13). AEDS affects up to one in 10 children. Onset is usually in the first weeks and months of life and, while most affected people enter spontaneous remission, the dermatitis may persist into adult life. The condition causes major impairment of quality of life. Epidemiological studies show that parental AEDS confers a higher risk of atopic dermatitis to offspring than parental allergic asthma or allergic rhinitis (14). These findings indicate the existence of genes specific for AEDS. To give an example of a European country, Schäfer et al. (15) found a prevalence of AEDS of 10.4% in Germany. The prevalence was found to be significantly higher in East (12.9%) as compared to West (8.2%) Germany. This is explained by an increase of the intrinsic form of AEDS (see below), that was almost twice as high in the East with 8.5% as compared to 4.7% in the West (15). The differences, however, are decreasing. Von Mutius et al. (16) compared the prevalence of asthma in schoolchildren from the cities of Munich and Leipzig in the reunified Germany. The level of pollution was far higher in Leipzig. Surprisingly, there was significantly less allergic disease in the more heavily polluted city of Leipzig than in Munich. In addition, the prevalence of atopy has risen steadily in East Germany since lifestyle and environment have become more westernized. This suggests that the increase in the prevalence of allergic disease is probably due to factors associated with a western lifestyle (16). Schultz-Larsen et al. (17) determined the increased prevalence of AEDS in Northern Europe by a cross-sectional questionnaire study. They found a frequency of AEDS of between 9% and 16% in 7-year-old-school children in Denmark, Germany and Sweden. Comparing their results with previous studies, Schultz-Larsen et al. (18) found a rising cumulative incidence rate of atopic eczema/dermatitis syndrome: In children born before 1960 it was 2% to 3%, during the 1960s it rose to 4% to 8%. In the 1970s, rates from 9% to 12% were recorded, and for those born in the 1980s, at least 15% to 20% might develop AEDS during childhood as stated in 1986. This continuously increasing frequency of AEDS during the past 30–40 years suggests that widespread environmental factors originating from the industrialized world are operating in genetically susceptible persons (18). So far, genome-wide scans for genes predisposing to allergic diseases have been performed mostly focussing on asthma and phenotypes characterized by high IgE levels (see below). Concerning atopic eczema/dermatitis syndrome (atopic eczema: OMIM *603165), the role of genetic factors in this disease is demonstrated by twin studies, which consistently showed a higher concordance rate in monozygotic (MZ) twins compared to dizygotic (DZ) twins. However, disease concordance in MZ twins is far from complete, a fact which highlights the substantial role of environmental factors acting on the basis of genetic susceptibility. However, contrary to frequent belief, interpretation of twin studies is not unequivocal, due to different concepts and methodological approaches and their limitations (method of ascertainment and its associated bias, proband or pair-wise concordance rates, environmental variance components in MZ and DZ, etc.). Whereas all twin studies essentially show the same pattern of concordance rates, additional criticism can be directed against older studies since they were based on either ill-defined twin populations (19, 20), or did not address specifically AEDS (21, 22). A careful and targeted twin study from Denmark (18) demonstrated pairwise concordance rates of 0.77 in MZ and 0.15 in DZ twins, and subsequently, on a similar cohort some years later (23), 0.72 and 0.23, respectively. The decrease in MZ concordancy, and the concomitant increase in DZ concordance rate, may reflect the gain of exogenous factors, which by the same token is responsible for the gain in overall prevalence of the disease. The cumulative incidence rate for a seven year period was 0.03 for the birth cohort 1960–64, and 0.12 for the cohort 1975–79 (23). The importance of genetic factors in AEDS is underlined by the finding that a positive parental history is the strongest risk factor for AEDS; the incidence rate is doubled if AEDS is present in one parent, and tripled if both parents are affected (24). In order to determine the relative contribution of genetic and the environmental factors on the occurrence of atopic diseases, Diepgen and Blettner (25) performed a family study on AEDS showing an odds ratio (OR) of 2.16 (95% CI 1.58–2.96) for AEDS if no distinction was made between the degree of relationship and an OR of 3.86 (95% CI 2.10–7.09) for siblings of an affected index case. The odds ratio describes the association between categorical or binary variables such as presence or absence of a disease between groups. In our context, an odds ratio greater than 1 reflects familial aggregation. Another study examined the OR in German families where one parent is also suffering from AEDS. Then the disease risk shows an OR between 3.4 (95% CI 2.6–4.4) and 6.2 (95% CI 3.3–11.5) (26, 27). Gene Mapping studies of familial atopy have identified several chromosomal regions containing genes predisposing to atopy. However, the data for candidate regions do not show consistency, which may presumably be due either to genetic heterogeneity or to clinical (phenotypic) heterogeneity, or to both. This is a common finding in complex diseases, and additionally may be due to the multicomponent nature of this genetic etiology (28). Several candidate loci and genes for atopy have been suggested on the bases of family studies with patients suffering from allergic asthma. Evidence for inheritance through maternally transmitted alleles and atopy at different loci has been reported, including chromosomes 4q35.2, 11q13, 16q24.1 (29). An early set of studies searching for evidence of atopy and asthma-associated genes in several different populations exists for chromosome 5q31-q35, a region containing multiple candidate genes for allergy and asthma, including a clustered family of cytokine genes, i.e., IL4, which play important interactive roles in the allergic inflammatory response. In the Pennsylvania Amish population, evidence for linkage of total IgE, but not specific IgE, was found within the 5q31.1 region (30). Further studies suggested that IL4 and/or nearby genes in 5q31.1 regulate IgE production in a noncognate fashion (31). Linkage of total IgE to 5q31-q35 is supported by studies of Meyers et al. (32). Malerba et al. (33) showed significant allele sharing for the locus of the high affinity IgE receptor beta chain (chromosome 11q13) in affected sib-pairs with positive skin prick test who where suffering from bronchial hyperresponsiveness. In the examined population of atopic children in Italy the commonly reported Ile181Leu mutation (34) was not replicable. These findings suggest that different genetic factors might vary within and between different populations. A genom-wide screen in positive skin prick test Hutterites, a founder population in the USA with European ancestry, provided evidence for at least three atopy-susceptibility loci on chromosomes 1, 6 and 16 (1p32–31, 6p21, 16p12.1) (35). In the same Hutterite population, five regions showed possible linkage to asthma phenotypes (5q23–31, 12q15–24.1, 19q13, 21q21 and 3p24.2–22, the latter reported for the first time in the Hutterites) (36). In a single center study of multicase asthma families the role for HLA class II polymorphism in influencing allergen-specific and nonspecific IgE production was supported (37). Grasemann et al. (38) suggest that variants of the NOS1 gene located on chromosome 12q24 may be one source of genetic risk for asthma and atopy, whereas a genomewide screen for asthma susceptibility loci in three U.S. populations showed evidence for linkage at 1q32, 6p21 and 11q21 for the Hispanic, the European American and the African American, respectively (39). Linkage of atopy to a genetic marker on 11q13 was reported by Cookson et al. (40). The beta chain of the high-affinity receptor for IgE (FCER1B, OMIM*147138) was localized to the same region, and polymorphism with the gene related to atopy (41). Variants of this gene seem to exert a regulatory effect on IgE production and show significant association with positive IgE responses in a random patient sample (34). Cookson et al. (42) provided the first evidence for a maternal effect to atopy at the 11q13 marker for the β subunit of the high affinity IgE receptor FcεRI. In their study, a gene was assigned for atopy to chromosome 11q by linkage to the marker D11S97. These results show a significant sharing of maternally inherited alleles in region 11q13 in sib-pairs with atopic IgE responsiveness. Here, the transmission of atopy at the chromosome 11q locus is detectable only through the maternal line, because no excess sharing of paternally derived alleles was seen. The pattern of inheritance is consistent either with paternal genomic imprinting or with maternal modification of developing immune responses (42). In a very recent study, evidence for linkage of AD (AEDS) to chromosome 3q21 near marker D3S3606 was detected (43). It was only under the assumption of paternal imprinting that significant evidence for linkage of allergic sensitization was detected to this locus, indicating that this trait is predominantly transmitted by the mother (43). However, atopy seems to be inherited paternally in some families, and the offspring of two atopic parents have a greater chance of atopy than children of a single affected parent (44). Coleman et al. (45) proved the reported genetic linkage between atopic respiratory disease and chromosomal region 11q13 in families with patients suffering from AEDS. In this study, a major susceptibility locus for atopy in the 11q13 region was excluded by linkage analyzes. In some of the examined families, maternal imprinting seemed to be demonstrated, therefore here the possibility of a paternal influence on the inheritance of atopy cannot be excluded. Cox et al. (46) tested several polymorphisms within the high-affinity receptor b chain gene FCER1B (11q13) for association to AEDS and confirmed association of FCER1B RsaI polymorphisms with the disease. The association was demonstrated only with maternally derived alleles. These controversial linkage findings between atopy and markers at chromosome 11q13 were discussed by Folster-Holst et al. (47) who in their study of 12 families support the findings of the IgE high-affinity receptor gene FCER1B at 11q13. Another coding variant of the FCER1B gene (Gly237Glu) is associated with atopic asthma and very high total serum IgE levels (48). From a pathophysiological point of view, it is difficult to consider FCER1B as a crucial element since FcεRI expressing antigen presenting cells (APC) – which are suspected to play a dominant role in this disease – lack this receptor subunit (12). In order to identify relevant genes of IgE responsiveness, a positional cloning approach was started by the German asthma genetics group (49). The results showed that it is that the factors for genetic of IgE cannot be described by the of a single major gene as several linkage regions were identified for examined specific IgE for linkage regions on chromosomes 1, 16 and seem to be more to influence the IgE at the level than at the level of into of et al. characterized and the gene for the human of the IgE receptor FcεRI on chromosome between the of the of the receptor that genes have from a common by and that they a gene In to being localized on the same both genes show an of their A high level of is found in three of their and the between are and are for of their of may also a family of related The chromosome 5q31.1 et al. families with multiple of early AEDS for of genes from the candidate regions on chromosomes gene 11q13 IgE receptor and receptor A major locus that causes a to atopy was found at the that this chromosomal region a gene predisposing to AEDS. there are different genes that – with environmental factors – determine whether atopy as asthma, or The reported linkage to 11q13 not be supported by the findings of this study. association with candidate polymorphisms in the and genes were not found here chromosomal regions in AEDS, et al. found in a more recent study evidence for linkage in the region of as as in the 11q13 and the region in families with at least two siblings affected with AEDS The chromosome 5q31.1 the which several important cytokine genes such as IL4, and et al. showed that an IL4 a to at is associated with serum IgE levels in atopic et al. polymorphisms within the region of IL4 and tested their association with AEDS. The polymorphism was identified and with the known polymorphism of the polymorphisms predisposed to early AEDS by but the study linkage for the Evidence for linkage and association for AEDS in German and families was observed for markers on chromosome in the on both and in the German population The gene on chromosome was also suggested as a candidate gene for atopic diseases. A receptor allele was identified and found to be associated with atopy by et al. The relative risk of atopy persons positive for a allele was et al. a to maternal inheritance of a gene in the chromosome region which the risk for IgE responsiveness. The most candidate gene in this region is the gene for the receptor This receptor of an chain and the common polymorphisms have been and and were found to be of The variant has been reported to receptor to and increased of and IgE production the variant of was associated with the development of atopic asthma. The of the receptor results in increased of the of 6 et al. families with children and found no association with variants of the whereas polymorphisms in the receptor chain have been reported to be associated with adult AEDS in by et al. who a locus for atopy on chromosome and proved the reported of and variants in the They stated this gene be a candidate gene for AEDS. It also be that is a crucial cytokine for the of the of the of the high affinity IgE receptor in and may also be of importance in the pathophysiological concept of AEDS. chromosome the presence of the genes for and factor known as factor or this region an candidate for atopy susceptibility loci (4). this one has to into that our pathophysiological understanding no more support cells being the major in the of AEDS. markers in chromosome evidence was found for linkage of high total IgE by both and transmission analyzes. the transmission test to children of German with high IgE and their a study of high IgE provided evidence for linkage of high IgE with (31). The German allergy study genetic markers of atopy in on chromosome as as on chromosomes and A mutation in the of the gene cytokine has been identified of receptor allergic and AEDS. The mutation of the gene results in a for the factor The point mutation at is more frequent in individuals of African compared to Cookson et al. the results of a screen for childhood AEDS with serum IgE CI in which linkage to AEDS on chromosomes and was Surprisingly, regions very to known as the described AEDS locus on chromosome 3q21 The results indicate that AEDS is by genes with effects on skin In this it is of that immune to the same chromosomal bowel disease for example to chromosomes 12 and 16 in a very similar to asthma-associated loci 20% of patients from a skin disease which the skin and pattern of allergic AEDS, but is not associated with total levels and sensitization environment or the pathogenesis of this AEDS intrinsic atopic dermatitis by seems to be different from the disease known as allergic form of AEDS atopic to et al. as a clinical AEDS, the of and low total levels in with for and allergens and as as prick test results for and absence of atopic diseases such as allergic or allergic bronchial asthma. patients may be a AEDS, but during the they may to be as allergic and is similar to allergic AEDS, the inflammatory in seems to be different from allergic AEDS and can be by of cells suggest that the presence of allergen-specific IgE be a for the of AEDS and that the form be as to atopy the AEDS a sensitization against environmental allergens is not To the pathogenesis still to be examined in et al. patients that the of and patients with AEDS were of all AEDS patients to the AEDS, at least the is be from the and of atopic associated with IgE The different molecular pathogenesis of AEDS suggests a different etiology, i.e., genetic factors, most at different chromosomal as by linkage or linkage studies allergic AEDS Since the distinction between allergic and AEDS is a concept not much is known about and formal However, both being that however, do in there are no twin studies specifically directed AEDS, and hence the degree of genetic is unknown in this to show a degree of in families and have to the AEDS being a This if for not a degree of genetic since components will to a low while a risk may be to the the of in genetic will in of genetic factors in as compared to allergic AEDS, or atopic In the absence of exogenous factors, intrinsic factors will have to exert a relatively In the of the form of AEDS, genetic factors most are intrinsic factors. This is the of the of multifactorial However, it to be seen whether this in of AEDS. There is no a to that genetic factors play a role in than in allergic AEDS. and the atopic are to from multifactorial with between several genetic and environmental factors. A number of candidate genes have been and linkage has been found between atopy and some chromosomal regions characterized by genetic markers (see The genetic studies on atopic diseases to the of have provided almost results about to chromosomal a few of which be in more than one study cytokine of However, of results in linkage of complex disease do and and hence a lack of is not evidence for a positive The genetic findings in atopy may be very different according to and and they be in different population The of complex genetics is to single of an for disease susceptibility to and II several and may be affected be to a locus for of the genetic effect on AEDS of by linkage and linkage to the sample have been to an for to data on the genetics of asthma and allergy where of linkage studies, gene studies and to relevant are at there is still a great for understanding the complex genetic on which environmental to AEDS, for an understanding of pathogenesis the for and